{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:54:41Z","timestamp":1790794481316,"version":"4.1.0"},"reference-count":56,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"869","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2026,9,30]]},"abstract":"<jats:p>\n                    KRAS G12C (Gly\n                    <jats:sup>12<\/jats:sup>\n                    \u2192Cys) inhibitors (G12Cis) have improved outcomes for patients with\n                    <jats:italic toggle=\"yes\">KRAS<\/jats:italic>\n                    G12C\u2013mutated non\u2013small cell lung cancer (NSCLC), but their clinical benefit is limited by the emergence of resistance mechanisms. Here, we demonstrate that combining the RAF\/MEK clamp avutometinib and the focal adhesion kinase (FAK) inhibitor defactinib with a G12Ci enhanced antitumor activity by deepening mitogen-activated protein kinase (MAPK) pathway suppression and simultaneously inhibiting adaptive resistance pathways induced by G12Ci and avutometinib treatment, including FAK and PI3K signaling. In\n                    <jats:italic toggle=\"yes\">KRAS<\/jats:italic>\n                    G12C NSCLC mouse models, the triplet combination produced greater tumor growth inhibition than either sotorasib alone or the sotorasib plus avutometinib doublet. Moreover, in\n                    <jats:italic toggle=\"yes\">KRAS<\/jats:italic>\n                    G12C NSCLC mouse models resistant to sotorasib, the addition of avutometinib and FAK inhibition restored sensitivity to sotorasib and increased both the depth and durability of antitumor responses. Collectively, these findings demonstrate that concurrent targeting of KRAS G12C, RAF\/MEK, and FAK signaling can overcome multiple resistance mechanisms and provide a strong rationale for the clinical evaluation of sotorasib, avutometinib, and defactinib in patients with\n                    <jats:italic toggle=\"yes\">KRAS<\/jats:italic>\n                    G12C\u2013mutated NSCLC (RAMP 203; NCT05074810).\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.aea4608","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:58:33Z","timestamp":1790791113000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["FAK inhibitor and RAF\/MEK clamp avutometinib enhance KRAS G12C inhibitor efficacy in preclinical models of non\u2013small cell lung cancer"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8109-2813","authenticated-orcid":true,"given":"Silvia","family":"Coma","sequence":"first","affiliation":[{"name":"Verastem Oncology, Needham, MA 02494, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1753-3765","authenticated-orcid":true,"given":"Monica","family":"Musteanu","sequence":"additional","affiliation":[{"name":"Experimental Oncology Group, Centro Nacional de Investigaciones Oncol\u00f3gicas (CNIO), 28029 Madrid, Spain."},{"name":"Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Universidad Complutense de Madrid, 28040 Madrid, Spain."},{"name":"Health Research Institute of the Cl\u00ednico San Carlos Hospital (IdISSC), 28040 Madrid, Spain."},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de C\u00e1ncer (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina Caffarra","family":"Malvezzi","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino 10126, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan R.","family":"Jamieson","sequence":"additional","affiliation":[{"name":"Verastem Oncology, Needham, MA 02494, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8060-5058","authenticated-orcid":true,"given":"Enrico","family":"Patrucco","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino 10126, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8456-8159","authenticated-orcid":true,"given":"Alessia","family":"Mira","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino 10126, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4006-5285","authenticated-orcid":true,"given":"Julien","family":"Dilly","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyue","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5486-6844","authenticated-orcid":true,"given":"Ana","family":"Fern\u00e1ndez-Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Experimental Oncology Group, Centro Nacional de Investigaciones Oncol\u00f3gicas (CNIO), 28029 Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandra","family":"L\u00f3pez-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Experimental Oncology Group, Centro Nacional de Investigaciones Oncol\u00f3gicas (CNIO), 28029 Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0701-6203","authenticated-orcid":true,"given":"Andrew J.","family":"Aguirre","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1480-2624","authenticated-orcid":true,"given":"Mariano","family":"Barbacid","sequence":"additional","affiliation":[{"name":"Experimental Oncology Group, Centro Nacional de Investigaciones Oncol\u00f3gicas (CNIO), 28029 Madrid, Spain."},{"name":"Health Research Institute of the Cl\u00ednico San Carlos Hospital (IdISSC), 28040 Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4122-701X","authenticated-orcid":true,"given":"Chiara","family":"Ambrogio","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino 10126, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0263-474X","authenticated-orcid":true,"given":"Jonathan 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